Click chemistry is a newer approach to the synthesis of drug-like molecules
that can accelerate the drug discovery process. Sharpless, et al. defined what
makes a click reaction as one that is wide in scope and easy to perform, uses
only readily available reagents, and is insensitive to oxygen and water. Of
the reactions comprising the click universe, the “perfect” example is the Huisgen
1,3-dipolar cycloaddition of alkynes to azides to form 1,4-disubstituted-1,2,3-triazoles
(Scheme 1).1-4

Copper (I) species are powerful catalysts for the formation of 1,2,3-triazoles
from azides and alkynes. The general thermodynamic instability of Cu(I) however,
results in easy oxidation to Cu(II) and/or disproportionation to Cu(0) and Cu(II).1-4
TBTA, Tris-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine, also known
as tris-(benzyltriazolylmethyl)amine, is a stabilizing
ligand for Cu(I) developed by Tim Chan in Sharpless’ lab. TBTA protects Cu(I)
from oxidation and disproportionation, while enhancing its catalytic activity.5
A C3-symmetric derivative, TBTS is an extremely useful ligand for azide-alkyne
cycloaddition with ~106 fold of rate acceleration.
Its tetradentate binding ability is able to completely envelop the Cu(I) center,
leaving no free binding sites available for potential destabilizing interaction.
Reactions are typically carried out with 1-2 mol % Cu(I) and TBTA without having
to exclude oxygen and water.5